Interferons are relatively small, single-chain glycoproteins released by cells invaded by viruses or certain other substances. Interferons are presently grouped into three major classes, designated leukocyte interferon (interferon-alpha, .alpha.-interferon, IFN-.alpha.), fibroblast interferon (interferon-beta, .beta.-interferon, IFN-.beta.), and immune interferon (interferon-gamma, .gamma.-interferon, IFN-.gamma.). In response to viral infection, lymphocytes synthesize primarily .alpha.-interferon (along with a lesser amount of a distinct interferon species, commonly referred to as omega interferon, IFN-.omega.), while infection of fibroblasts usually induces .beta.-interferon. .alpha.- and .beta.-interferons share about 20-30 percent amino acid sequence homology. Thus, the gene for human IFN-.beta. lacks introns, and encodes a protein possessine 29% amino acid sequence identity with human IFN-.alpha.I, suggesting that IFN-.alpha. and IFN-.beta. genes have evolved from a common ancestor (Taniguchi et al., Nature 285, 547-549 (1980)). By contrast, IFN-.gamma. is not induced by viral infection, rather, is synthesized by lymphocytes in response to mitogens, and is scarcely related to the other two types of interferons in amino acid sequence. Interferons-.alpha., .beta. and .omega. are known to induce MHC Class I antigens, and are referred to as type I interferons, while IFN-.gamma. induces MHC Class II antigen expression, and is also referred to as type II interferon.
A large number of distinct genes encoding different species of IFNs-.alpha. have been identified. Alpha interferon species identified previously fall into two major classes, I and II, each containing a plurality of discrete proteins (Baron et al., Critical Reviews in Biotechnology 10, 1790190 (1990); Nagata et al., Nature 287, 401-408 (1980); Nagata et al., Nature 284, 316-320 (1980); Streuli et al., Science 209, 1343-1347 (1980); Goeddel et al., Nature 290, 20-26 (1981); Lawn et al., Science 212, 1159-1162 (1981); Ullrich et al., J. Mol. Biol. 156, 467-486 (1982); Weissmann et al., Phil. Trans. R. Soc. Lond. B299, 7-28 (1982); Lund et al., Proc. Natl. Acad. Sci. 81, 2435-2439 (1984); Capon et al., Mol. Cell. Biol. 5, 768 (1985)). The various IFN-.alpha. species include IFN-.alpha.A (IFN-.alpha.2), IFN-.alpha.B, IFN-.alpha.C, IFN-.alpha.C1, IFN-.alpha.D (IFN-.alpha.1), IFN-.alpha.E, IFN-.alpha.F, IFN-.alpha.G, IFN-.alpha.H, IFN-.alpha.I, IFN-.alpha.J1, IFN-.alpha.J2, IFN-.alpha.K, IFN-.alpha.L, IFN-.alpha.4B, IFN-.alpha.5, IFN-.alpha.6, IFN-.alpha.74, IFN-.alpha.76 IFN-.alpha.4a), IFN-.alpha.88, and alleles of these species. According to our current knowledge, the IFN-.alpha. family consists of 13 expressed alleles producing 12 different proteins that exhibit remarkably different biological activity profiles. Pestka, S., Semin. Oncol. 24(suppl. 9), S9-4-S9-17 (1997).
Interestingly. while only a single human IFN-.beta. gene has been unequivocally identified, bovine IFN-.beta. is encoded by a family of five or more homologous, yet distinct genes.
Interferons were originally produced from natural sources, such as buffy coat leukocytes and fibroblast cells, optionally using known inducing agents to increase interferon production. Interferons have also been produced by recombinant DNA technology.
The cloning and expression of recombinant IFN-.alpha.A (rIFN-.alpha.A, also known as IFN-.alpha.2) was described by Goeddel et al., Nature 287, 411 (1980). The amino acid sequences of rIFNs-.alpha.A, B, C, D, F, G, H, K and L, along with the encoding nucleotide sequences, are described by Pestka in Archiv. Biochem. Biophys. 221, 1 (1983). The amino acid sequences and the underlying nucleotide sequences of rIFNs-.alpha.E, I and J are described in British Patent Specification No. 2,079,291, published Jan. 20, 1982. Hybrids of various IFNs-.alpha. are also known, and are disclosed, e.g. by Pestka et al., supra. Nagcata et al., Nature 284, 316 (1980), described the expression of an IFN-.alpha. gene, which encoded a polypeptide (in non-mature form) that differs from rIFN-.alpha.D by a single amino acid at position 114. Similarly, the cloning and expression of an IFN-.alpha. gene (designated as rIFN-.alpha.2) yielding a polypeptide differing from rIFN-.alpha.A by a single amino acid at position 23, was described in European Patent Application No. 32 134, published Jul. 15, 1981.
The cloning and expression of mature rIFN-.beta. is described by Goeddel et al., Nucleic Acids Res. 8, 4057 (1980).
The cloning and expression of mature rIFN-.gamma. are described by Gray et al., Nature 295, 503 (1982).
IFN-.omega. has been described by Capon et al., Mol. Cell. Biol. 5, 768 (1985).
IFN-.tau. has been identified and disclosed by Whaley et al., J. Biol. Chem. 269, 10864-8 (1994).
All of the known IFNs-.alpha., -.beta., and -.gamma. contain multiple cysteine residues. These residues contain sulfhydryl side-chains which are capable of forming intermolecular disulfide bonds. For example, the amino acid sequence of mature recombinant rIFN-.alpha.A contains cysteine residues at positions 1, 29, 98 and 138. Wetzel et al., Nature 289, 606 (1981), assigned intramolecular disulfide bonds between the cysteine residues at positions 1 and 98, and between the cysteine residues at positions 29 and 138.
Antibodies specifically binding various interferons are also well known in the art. For example, anti-.alpha.-interferon agonist antibodies have been reported by Tsukui et al., Microbiol. Immunol. 30, 112901139 (1986); Duarte et al., Interferon-Biotechnol. 4, 221-232 (1987); Barasoaian et al., J. Immunol. 143, 507-512 (1989); Exley et al., J. Gen. Virol. 65, 2277-2280 (1984); Shearer et al., J. Immunol. 133, 3096-3101 (1984); Alkan et al., Ciba Geigy Foundation Symposium 119, 264-278 (1986); Noll et al., Biomed. Biochim. Acta 48, 165-176 (1989); Hertzog et al., J. Interferon Res. 10 (Suppl. 1) (1990); Kontsek et al., J. Interferon Res. (special issue) 73-82 (1991), and U.S. Pat. No. 4,423,147 issued Dec. 27, 1983.
The actions of type I interferons appear to be mediated by binding to the IFN-.alpha. a receptor complex on the cell surface. This receptor is composed of at least two distinct subunits identified as IFN-.alpha.R1 (Uze et al., Cell 60, 225-234 [1990]) and IFN-.alpha.R2 (Novick et al. Cell 77, 391-400 [1994]), each having 2 and 3 spliced variants, respectively. IFN-.alpha.R2 is the binding subunit of the known type interferons, whereas IFN-.alpha.R1 contributes to higher affinity binding and signaling. The engagement of receptors by ligand binding activates Janus family kinases (JAK) and protoplasmic latent signal transducers and activators of transcription (STAT) proteins by tyrosine phosphorylation. Activated STATs translocate to the nucleus in forms of complexes and interact with their cognitive enhancer elements of IFN-stimulated genes (ISGs). leading to a corresponding transcription activation and biological responses. Darnell et al., Science 264, 1415-21 (1994). However, despite similarities in their binding properties, the biological responses stimulated by type I interferons are significantly different.
Interferons have a variety of biological activities, including antiviral, immunoregulatory and antiproliferative properties, and are, therefore, of great interest as therapeutic agents in the control of cancer, and various viral diseases. Interferons have been implicated in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematoses, Behcet's disease, insulin-dependent diabetes mellitus (IDDM, also referred to as type I diabetes). It has been demonstrated in a transgenic mouse model that .beta. cell expression of IFN-.alpha. can cause insulitis and IDDM, and IFN-.alpha. antagonists (including antibodies) have been proposed for the treatment of IDDM (WO 93/04699, published Mar. 18, 1993). Impaired IFN-.gamma. and IFN-.alpha. production has been observed in multiple sclerosis (MP) patients. An acid-labile IFN-.alpha. has been detected in the serum of many AIDS patients, and it has been reported that the production of IFN-.gamma. is greatly suppressed in suspensions of mitogen-stimulated mononuclear cells derived from AIDS patients. For a review see, for example, Chapter 16, "The Presence and Possible Pathogenic Role of Interferons in Disease", In: Interferons and other Regulatory Cytokines, Edward de Maeyer (1988, John Wilet and Sons publishers). Alpha and beta interferons have been used in the treatment of the acute viral disease herpes zoster (T. C. Merigan et al., N. Engl. J. Med. 298, 981-987 (1978); E. Heidemann et al., Onkologie 7, 210-212 (1984)), chronic viral infections, e.g. hepatitis B infections (R. L. Knobler el al., Neurology 34, 1273078 (1984); M. A. Faerkkilae et al., Act. Neurol. Sci. 69, 184-185 (1985)). rIFN-.alpha.-2a (Roferon.RTM., Roche) is an injection formulation indicated in use for the treatment of hairy cell leukemia and AIDS-related Kaposi's sarcoma. Recombinant IFN-.alpha.-2b (Intron.RTM. A. Schering) has been approved for the treatment of hairy cell leukemia, selected cases of condylomata acuminata, AIDS-related Kaposi's sarcoma, chronic hepatitis Non-A, Non-B/C, and chronic helatitis B infections is certain patients. IFN-.gamma.-1b (Actimmune.RTM., Genentech. Inc.) is commercially available for the treatment of chronic granulomatous disease.
For further information about the biologic activities of type I IFNs see, for example, Pfeffer, Semin. Oncol. 24(suppl 9), S9-63-S9-69 (1997).